tbuckley/cabot-search huggingface dataset:
Body mass index and venetoclax-hypomethylating agent induction therapy for acute myeloid leukemia.
Authors: Julian J Weiss, Henry Le, Sonal Agarwal, Nikolai Alexandrovich Podoltsev, Amer Methqal Zeidan, Rory Shallis
Journal: Journal of Clinical Oncology (2022)

e19038 Background: Frontline Ven-HMA dosing is imperfectly estimated with HMA using body surface area (BSA) and Ven not BSA/weight-based. Not much is known if elevated body-mass-index (BMI) reduces drug exposure and impacts clinical outcomes with Ven-HMA. We sought to investigate the effectiveness of Ven-HMA in pts with elevated BMI and hypothesized no negative impact on outcomes. Methods: We retrospectively reviewed the records of pts with AML treated with frontline Ven-HMA from 12/2018-11/2021. The primary outcome was composite response rate (CR/CRi) as defined by 2017 ELN criteria. Pearson’s χ 2 tests and Wilcoxon rank tests were used for bivariate analyses. Kaplan-Meier methods were used to calculate OS. Results: We identified 63 pts treated with frontline Ven-HMA, among whom 20 had a normal BMI (&lt;25 kg/m 2 ), 27 were overweight (BMI 25-29 kg/m 2 ), and 16 were obese (BMI&gt;30 kg/m 2 ). Median age was 73 (range 37-89) and there were no differences in baseline patient- and disease-specific factors. The cohort overall was enriched for complex karyotype and TP53-mutated disease (46% and 33%, respectively), but without intergroup differences. Increasing BMI was associated with more HMA naivety and appeared to be associated with more antifungal use during induction (BMI &lt;25: 60%, BMI &gt;30: 88%; p=0.07) with similar rates of moderate/strong CYP3A4 inhibition. Early mortality (within 8-weeks of Ven-HMA), was greater in obese pts, but not significantly so (BMI&lt;25: 20%; BMI&gt;30: 31.3%; p=0.45). CR/CRi rate was similar among groups (BMI&lt;25: 40%; BMI 25-29: 52%; BMI&gt;30: 44%; p=0.71), as was ORR ( p=0.14). A sub-analysis excluding pts with prior HMA did not affect the parity in rate of CR/CRi in normal weight or obese pts (40% vs 44%, p=0.83) (Table). Conclusions: Our study showed that increasing BMI appears to have no negative influence on response to frontline Ven-HMA. However, it remains unclear whether increased BMI affects drug exposure, so dedicated studies are needed.[Table: see text]
Evaluating the impact of performance status criteria on minority eligibility for oncology clinical trials.
Authors: Sudip Bhandari, Jeremy Mann, Jitesh Chawla, Prerna Jain, Margot Knight, Charles Lagor, Judith Mueller, Paola Raska, Steve Southwick, Warren Whyte
Journal: Journal of Clinical Oncology (2022)

e18701 Background: Restrictive criteria contribute to low enrollment in clinical trials. These criteria can also amplify health disparities by reducing the racial and ethnic diversity of the cohort. Many studies show that minority patients exhibit worse Eastern Cooperative Oncology Group (ECOG) performance status than white patients. Based on clinical trial data, some researchers have hypothesized that relaxing the ECOG criterion in clinical trial criteria could improve the diversity of the cohort. However, little research exists to measure ECOG’s impact on minority eligibility. Using Real-World Data (RWD), we evaluate whether relaxing the ECOG criterion monotonically increases the racial diversity of the cohort in oncology clinical trials. Methods: We used ConcertAI’s database of US oncology Electronic Medical Record (EMR) data, which includes clinical data from CancerLinQ Discovery™. We conducted sensitivity analyses for the inclusion criteria of 16 different clinical trials across multiple cancer indications. For each trial, we created five cohorts based on five different ECOG score upper limits. For example, the first cohort only included patients who had an ECOG of 0, the second cohort included patients with an ECOG of 0 or 1, etc. We then recorded the percentage of non-white patients for the resulting cohorts. We ran simple linear regressions to measure whether the change in the percentage of non-white patients was statistically significant. Results: Relaxation in ECOG status led to no uniform change in the racial diversity of patients across the 16 trials. The limited changes we did observe were not statistically significant. Conclusions: Our findings suggest that improving diversity will require more than just relaxing ECOG restrictions, and a multi-faceted approach may be needed. Future research exploring the relationship between ECOG and diversity should control for potential confounders like age, gender, and comorbidities using multivariable models. Such research needs to also account for patients with unknown race and ECOG, which represented large parts of our study population. Such research could elucidate whether the phenomenon observed in the general population—that minority patients tend to have worse performance status than whites—holds true in the sub-population of oncology patients.[Table: see text]
Global oncology and cancer disparities education.
Authors: Victoria Forbes, Anne Christine Buteau, Ilir Hoxha, Dafina Ademi Islami, John P. Palmer, Mary D. Chamberlin
Journal: Journal of Clinical Oncology (2022)

11006 Background: Comprehensive patient care requires an understanding of medical guidelines and the intersectional context of the patient’s identity and experiences. Hematology/Oncology programs must explicitly teach topics addressing various disparities of care to prepare trainees for informed care. We have developed a Global Oncology and Disparities of Cancer Program to address this gap. Methods: The telementoring program was piloted in 2019 at Dartmouth and has evolved to include didactics, discussion, and evaluations. Participants from across the globe include medical students, residents, Hematology/Oncology Fellows, Faculty, Global Health Scholars, and cancer clinicians. US Hematology/Oncology trainees from Dartmouth and the University of Connecticut consistently participate in the international program. Monthly sessions from September 2021-June 2022 include: Esophageal and GI Cancers in Rwanda, HCC and Cholangiocarcinomas, Gastric Cancer, ASCO International, Global Med ED in Haiti, Breast Cancer in Kosovo, Breast Cancer Risk Factor Prediction Tools Research, Shared Decision Making in Breast Cancer, Hemoglobinopathies, and Health Disparities and Capacity-Building in Rwanda. A pre-course survey was sent to identify participant’s demographics, barriers, and expectations. We will administer a post-course survey. Results: We have preliminary data for our ongoing project. However, we anticipate complete data collection and analysis before the ASCO Meeting. 24 participants were enrolled. 12 (52%) of the participants were located outside of the US in locations such as Haiti, Kosovo, and France. Using a 5-point Likert scale, 11 (46%) participants were “not at all” or only “slightly” aware of obstacles faced by Oncology patients and caregivers in seeking access to healthcare in the US. 7 (29%) participants answered similarly regarding those in low- and middle-income countries. Meanwhile, participants rated ‘’gaining different perspectives’’ as their most important reason for attending with 19 (79%) rating this as “very important” or above. For anticipated improvement from the course, understanding risk factors and cancer biology internationally and recognizing disparities in healthcare between domestic and international settings were the highest rated with 18 (75%) expecting an improvement to a “large degree” or higher. Conclusions: We developed a virtual educational experience to enhance participants’ ability to address disparities of care through challenging Global Oncology topics. Our course is ongoing however initial surveys show a need and desire for this content from participants. We intend to analyze the course surveys to shape future courses. This program can serve as a model for Hematology-Oncology programs to address unmet needs in the curriculum and prepare trainees to provide more complete care to improve cancer outcomes.
NeoTrio: Randomized trial of neoadjuvant (NAT) pembrolizumab (Pembro) alone, in sequence (SEQ) with, or concurrent (CON) with dabrafenib plus trametinib (D+T) in resectable BRAF-mutant stage III melanoma to determine optimal combination of therapy.
Authors: Georgina V. Long, Matteo S. Carlino, George Au-Yeung, Andrew John Spillane, Kerwin Frank Shannon, David E. Gyorki, Julie R. Howle, Sydney Ch'ng, Maria Gonzalez, Robyn P.M. Saw, Thomas Pennington, Serigne N. Lo, Richard A. Scolyer, Alexander M. Menzies
Journal: Journal of Clinical Oncology (2022)

9503 Background: Combination anti-PD(L)1 and BRAF/MEK-targeted therapy (TT) improves PFS in stage IV melanoma vs TT. In stage IV melanoma recent data suggest immunotherapy 1st until progression, rather than BRAF-TT, improves OS, and induction TT upfront adds little benefit. NeoTrio explored the optimal combination of BRAF-TT and anti-PD1 using the NAT platform in pts with stage III melanoma (NCT02858921). Methods: 60 pts with resectable, RECIST measurable stage III (no in-transit) BRAF V600 -mutant melanoma were randomized 1:1:1 to 3 arms of 6 wks of NAT followed by complete lymph node dissection (CLND): A) Pembro ALONE (200mg Q3W x 2); B) SEQ - D+T (150mg bd + 2mg od) for 1 wk followed by pembro (200mg x 2); C) CON – D+T+pembro (doses as SEQ). Pts had 46 wks pembro post-CLND. Primary endpoint was the pathological response rate (pRR) and pathological complete response (pCR) at wk 6. Secondary endpoints; RECIST RR at wk 6, event-free survival (EFS), RFS, OS, adverse events (AE) and translational endpoints. Results: At data cutoff 2 Jan 2022, 20 pts per arm had similar baseline characteristics; overall 42% female, med age 53 yrs, 82% BRAF V600E, 62% clinical N1b. Med f/u was 20 months (95% CI 17-31). The pCR rate and pRR were highest in CON arm, and similar in ALONE and SEQ arms (Table). Events (progression before surgery, recurrence after surgery or death) were highest in ALONE arm at this 1st analysis (Table). Assessment of the durability of path response subtypes in each arm is ongoing. Most common Rx related AE were fatigue (65%, 70%, 70%, ALONE, SEQ and CON respectively), pyrexia (0%, 25%, 85%) and rash (50%, 35%, 35%). Gd 3/4 AE occurred in 30%, 25% and 55%, respectively; pyrexia and hepatitis were common in CON during NAT. Rx interruptions during NAT occurred in 0, 3 and 19 pts, respectively; 1, 0 and 8 pts permanently discontinued. Post NAT surgical operability was the same or improved in 81%. Longitudinal analysis of melanoma tissue, microenvironment and microbiome is ongoing. Conclusions: CON D+T+pembro achieved the highest pRR, pCR rate, but with greater toxicity. Recurrences were seen in those with pCR/near pCR in BRAF-TT containing arms, but not in pembro ALONE, in keeping with previous data of NAT with checkpoint inhibitors vs BRAF-TT. Short course of D+T prior to PD1 did not improve path response, despite previous translational data showing increased tumour infiltrating T-cells early-during treatment with D+T. Follow up is ongoing. Clinical trial information: NCT02858921. [Table: see text]
Multi-omics analysis of locally advanced esophageal cell squamous carcinoma treated with radio-chemotherapy.
Authors: Hongwei Li, Jing Li, Xiaqin Zhang, Hua Liang, Liyan Ji, Xuan Gao, Xuefeng Xia
Journal: Journal of Clinical Oncology (2022)

e16106 Background: The incidence rate of esophageal cell squamous carcinoma (ESCC) increases every year worldwide. Although the molecular characteristics of locally advanced esophageal carcinoma have been extensively studied, TCR evolution dynamics before and after treatment in patients with ESCC undergoing radical radiotherapy and chemotherapy are unknown. Methods: In this study, we performed whole-exome sequencing (WES) and RNA sequencing (RNA-seq) on tumor tissues from 11 ESCC patients who received radiotherapy and chemotherapy. T cell receptor (TCR) sequencing was performed in 33 ESCC blood samples, which included three time points: pre-treatment, on-treatment and post-treatment. We compared TCR clonality and Shannon index among the pre-treatment, on-treatment and post-treatment ESCC patients using paired samples Wilcoxon test. The t test was uesd for statistical analysis comparing the clonality and clonal frequency between patients with mutant and wild-type gene. Results: The median TMB is 3.32 mutations/Mb (range 1-6 muts/Mb). We identified nine significantly mutant genes including TP53 (100%), MUC17 (55%), FLG (45%), FLG2 (36%), FOXN1 (27%), HIST1H1E (18%), VN1R1 (18%), RIPK3 (9%), and ZNF628 (9%). Clonality was significantly increased from pre-treatment to post-treatment (p = 0.008) and from on-treatment to post-treatment (p = 0.04). Two patients exhibited an continuous increase of TCR CDR3 (CHCLPAED_AGGGELFF) frequency in post-treatment compared to on-treatment patients. Three patients had elevated level of CDR3 amino acid sequence (CASSLDSNQPQHF) after treatment. To explore the effect of the mutant gene on the TCR clonal pattern, we found that the baseline clonality and clonal frequency in mutant FAT1 (MUT) were significantly lower than that in wild-type (WT) patients (p = 0.044 and p = 0.013, respectively), while they were not significant after treatment between FAT1-MUT and WT patients. Intriguily, in FAT1-MUT patients, the clonality and clonal frequency underwent therapy were higher than that at baseline. The results suggested that the FAT1-MUT patients might be sensitive to treatment and FAT1 might contribute to immune response upon radio-chemotherpay. During radio-chemotherapy, the clonality and clonal frequency in INTS1-MUT and LCT-MUT patients had the similar phenomenon to the FAT1-MUT patients. Interestingly, a higher clonal frequency was observed after radiotherapy and chemotherapy than that of pre-treatment (p = 0.0086) in patients with mutant KMT2D (an epigenetic modifier coding lysine methyl transferase 2D). Conclusions: TCRs is clonal expansion after radiotherapy and chemotherapy in ESCC, suggesting an immune-activated microenvironment after radio-chemotherapy. Our multi-omics analysis provided the basic TCRs dynamics and its genomic and epigenomic association during the radio-chemotherapy of esophageal cell squamous carcinoma.
Short-term efficacy of furmonertinib in treatment of NSCLC patients with EGFR exon20 insertion.
Authors: Xiaoyue Zhou, Huajie Dong, Peng Li, Changling Wu, Hongjun Lu, Mingzhe Xiao, Tong Zhou
Journal: Journal of Clinical Oncology (2022)

e21063 Background: EGFR is a key driver gene of lung cancer, in which exon 20 insertion (Ex20ins) mutation accounts for about 1-5%. However, the first- and second-generation EGFR-TKI had poor efficacy on patients with Ex20ins mutation (ORR = 6.9%, mPFS = 1.9 months, mOS = 12.9 months, DCR = 44.8%). Our study retrospectively observed the short-term efficacy and safety of furmonertinib in Chinese NSCLC patients with EGFR Ex20ins mutation. Methods: The study retrospectively collected 15 NSCLC patients with EGFR Ex20ins mutant who were treated in two medical institutions in Changzhou City, Jiangsu Province from April 2021 to December 2021. All patients received targeted therapy with furmonertinib. The last follow-up time was December 30, 2021. All patients received 160 mg furmonertinib orally until disease progression, drug intolerance, patient refusal or death. EGFR Ex20ins mutation was confirmed by ARMS or next generation sequencing (NGS). The patient's gender, age, score of Eastern Cooperative Oncology Group (ECOG), smoking history, pathological type, tumor stage, gene status and other basic clinical characteristics and adverse events (AES) were collected. The clinical efficacy was evaluated according to RECIST version 1.1, and the adverse events were evaluated according to the NCI-CTCAE version 5.0. SPSS 25.0 software was used to record and analyze the data. Results: All 15 patients had received ≥2 lines of therapy. The median age was 62 (25-80) years old, and there were 8 male patients (53.3%). Most patients had no smoking history (13 cases, 86.7%). ECOG score was mostly 1 (13 cases, 86.7%). In 15 patients, we found 10 different EGFR Ex20ins variants, among which p.A767_V769dup (n = 3) and p.A767_V769dup (n = 4) were more common. By the end of follow-up, 15 patients had completed at least one efficacy evaluation, and all had different degrees of tumor regression. No patient reached CR, 8 patients had PR and 7 patients had SD. This preliminary efficacy data showed that the overall ORR was 53.5% and DCR was 100%. No grade 3 or above adverse events were observed. The 3-months PFS rate was 100%. Conclusions: The results of this study in ≥2 lines patients treated with twice the conventional dose had a good curative effect (compared with 3 times of conventional dosage in FAVOUR study), which provided more treatment options for NSCLC patients in multiple lines of treatment and could alleviate part of their economic pressure, but the PFS and OS data still need further follow-up and verification of a larger sample size. The overall findings suggested that furmonertinib is a third generation EGFR-TKI with good efficacy and acceptable safety. Given the heterogeneity of EGFR Ex20ins mutation, the efficacy of targeted therapy may vary in different mutation types and requires further investigation.
International consensus guideline for anticancer drug dosing in kidney dysfunction (ADDIKD): A standardized approach to assessing kidney function in cancer patients and its application to anticancer drug dosing.
Authors: Geeta Sandhu, Josephine Adattini, Niamh O'Neill, Evangeline Armstrong Gordon, Aisling Kelly, Julia Shingleton, Winston S. Liauw, Robyn L. Ward
Journal: Journal of Clinical Oncology (2022)

e13518 Background: Anticancer drug dosing recommendations in kidney dysfunction are often empirical, based on non-standardised creatinine assays calculated via the Cockcroft-Gault equation, and lack applicability to globally accepted kidney dysfunction classifications. ADDIKD aims to provide a standardised approach to assessing kidney function in cancer patients, and to apply evidence and consensus-based recommendations to anticancer drug dosing in kidney dysfunction. Methods: An expert international multidisciplinary working group was established to develop anticancer drug dosing recommendations. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to critically appraise the quality and strength of evidence and formulate recommendations. The working group participated in workshops to achieve &gt; 80% consensus for a standardised approach to assessing and classifying levels of kidney function, its application to anticancer drug dosing in kidney dysfunction, and dosing recommendations for individual drugs. Upcoming public consultation will refine these recommendations and facilitate acceptance as an international benchmark. Results: Three key recommendations formed the basis of ADDIKD: Application of estimated glomerular filtration rate via the Chronic Kidney Disease-Epidemiology Collaboration equation (eGFR CKD-EPI ) to guide the assessment of kidney function, except where directly measured glomerular filtration rate (mGFR) is clinically necessary. Where the anticancer drug dose is dependent on kidney function and mGFR is not clinically necessary, eGFR CKD-EPI is suggested to guide dosing. Application of the Kidney Disease Improving Global Outcomes (KDIGO) Chronic Kidney Disease categories to guide stepwise dose adjustments of anticancer drugs in kidney dysfunction. A review of 2263 published articles and 177 registered product information monographs enabled 127 GRADE assessments by the working party, resulting in evidence and consensus-based dosing recommendations for 59 anticancer drugs. 'Quick reference’ dosing tables incorporated a traffic light system for alerting clinicians to caution around levels of kidney function and specific patient risk factors for consideration. Conclusions: eGFR CKD-EPI is the most accurate and convenient method for assessing kidney function in diverse populations (including cancer patients) and accounts for the standardisation of the creatinine assay. ADDIKD’s expert acceptance of this standardised approach, together with anticancer drug dosing recommendations in kidney dysfunction, provides a practical tool to establish clinically relevant dosing in this patient population.
DNA methylation profiling to determine the primary sites of metastatic cancers using formalin-fixed paraffin-embedded tissues.
Authors: Hongcang Gu, Shirong Zhang, Shutao He, Xin Zhu, Yunfei Wang, Qionghuan Xie, Wenxian Wang, Shenglin Ma, Jiantao Shi
Journal: Journal of Clinical Oncology (2022)

3079 Background: Metastatic cancers with uncertain primary sites account for a significant portion of new cases. Among them, 3-9% are eventually assigned to cancer of unknown primary (CUP) site after a comprehensive diagnostic workup. Accurate identification of the primary site is the starting point for cancer diagnosis worldwide, and it is critical to guide the subsequent treatments of metastatic cancers. Here we presented a new DNA methylation sequencing-based method to predict the tissues of origin for metastatic cancers, including CUP. Methods: Cancer diagnosis relies substantially on histological and immunohistochemical analyses of formalin-fixed paraffin-embedded (FFPE) tissues. To take advantage of sample accessibility, we developed an optimized and streamlined method that was particularly used to generate reduced represent bisulfite sequencing (RRBS) libraries for genome-wide DNA methylation profiling with degraded DNA fragments. After confirming that data quality generated using the new FFPE-RRBS method was comparable with regular RRBS, we created an RRBS database using 541 fresh frozen samples across ten most common cancer types and 58 tumor-adjacent normal tissues. By incorporating four distinct methylation summary scores and seven machine learning approaches, 28 models were trained and compared for multi-class classification using our database. Lastly, we selected the best classifier to predict the tissues of origin utilizing 249 FFPE samples across ten metastatic cancer types and 12 FFPE samples from CUP patients. Meanwhile, the classifier was also cross-validated using a DNA methylation microarray data set of 4702 patients diagnosed with corresponding primary cancers in the TCGA project. Results: FFPE-RRBS allowed to construct decent libraries with heavily degraded genomic DNA within 20 hours. Comparable DNA methylation metrics were obtained for the RRBS libraries of paired primary cancer tissues (fresh frozen vs. FFPE) and the libraries of paired FFPE samples derived from primary and metastatic tissues. Among the 28 methylation-based classifiers, the mean methylation-based LinearSVC model performed the best, achieving an overall accuracy of 81% with an AUC of 0.95 in determining the primary sites of 10 metastatic cancers. In a cross-validation assay using the TCGA data set of 4702 cancer patients, the overall prediction accuracy and AUC were 92% and 0.99, respectively. Lastly, our model successfully identified the tissues of origin in 10 of 12 CUP patients in a prospective study. Conclusions: The FFPE-RRBS is a novel method for efficient profiling of heavily degraded FFPE samples and the mean methylation-based LinearSVC model can predict the tissues of origin for metastatic cancers and CUP with high accuracy.